In the management of pain and discomfort, two kinds of drugs are widely used. The first kind is local anesthetics. Local anesthetics reversibly block the impulse conduction along nerves and other excitable membranes that primarily utilize sodium channels. Clinically, this action blocks the pain sensation from specific areas of the body.
Local anesthetics are weak bases. There are three major classes of local anesthetics, which are ester derivatives (such as cocaine, procaine etc.), amide derivatives (such as lidocaine, bupivacaine etc.), and others (such as dyclonine, pramoxine etc.). For therapeutic application, local anesthetics are usually made available as salts for reasons of solubility and stability. In the body, they exist either as the uncharged base (i.e., “free base”) or as a cation.
Local anesthetics generally consist of a lipophilic group (frequently an aromatic ring) connected by an intermediate chain (commonly including an ester or amide) to an ionizable group (usually a tertiary amine). Optimal activity requires a delicate balance between the lipophilic and hydrophilic strengths of these groups. Since ester links (as in procaine) are more prone to hydrolysis than amide links, esters usually have a shorter duration of action. (Miller & Hondeghem, (1995), “Local Anesthetics” in Basic & Clinical Pharmacology, 6th Edition, Ed. by Katzung).
Local anesthetics are usually administered by injection into the area of the nerve fibers to be blocked. Thus, absorption and distribution are not as important in controlling the onset of effect as in determining the rate of offset of anesthesia and the likelihood of central nervous system and cardiac toxicity. Topical application of local anesthetics, however, requires drug diffusion for both onset and offset of anesthetic effect. Therefore, the solubility and stability of the drug becomes major factors in determining the therapeutic effects of the drug. (Miller & Hondeghem, (1995), “Local Anesthetics” in Basic & Clinical Pharmacology, 6th Edition, Ed. by Katzung).
Among the local anesthetics, lidocaine, 2-(diethylamino)-N-(2,6-dimethylphenyl)-acetamide, is particularly known for its treatment of ventricular tachycardia (an arrythmia of the heart) as an intravenous injection solution. (See e.g., U.S. Pat. No. 3,968,205). Lidocaine is also widely used as a vasoconstrictor to reduce regional blood flow in topical applications or aerosols (such as nasal aerosols to reduce nasal congestion). (See eg., U.S. Pat. No. 5,534,242). In addition, lidocaine is known for its therapeutic effects in reducing post-herpetic neuralgia (PHN) nerve injury pain from shingles (herpes zoster and post herpetic neuralgia) and analogous neuropathies. For example, U.S. Pat. No. RE37,727 discloses methods employing lidocaine intradermal administration by transport lidocaine from the skin surface, using patches and dressings, into the skin.
Lidocaine base is freely lipid soluble. It is insoluble in water and thus not suitable for use in an aqueous suspension, requiring ethanol or the like to obtain a liquid solution. However, its salt form, lidocaine-HCl, is very soluble in water and alcohol. Thus, lidocaine-HCl is generally the form that is used for preparation of injection solution.
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs, probably due to their therapeutic properties as anti-inflammatories, analgesics, anti-pyretics, and anti-thrombolics and are used to treat a variety of clinical conditions manifesting such symptoms as pain, inflammation, fever, and to treat and prevent atherosclerosis. While these drugs are highly effective, oral administration of many NSAIDs can cause serious adverse effects such as gastrointestinal bleeding and ulceration, liver and kidney damages, and central nervous system and cutaneous disturbances, particularly after extended use. Therefore, in an effort to minimize the adverse effects associated with oral administration, non-oral delivery of NSAIDs has been extensively investigated in recent years.
Transdermal delivery, in particular, is an attractive option because it avoids the hepatic first-pass metabolism, reduces the side effects associated with oral administration, is associated with higher patient compliance and, in some cases, enhances therapeutic efficacy of the drug.
Transdermal delivery of NSAIDs is particularly useful for treatment of rheumatoid arthritis and related conditions, which are characterized by painful and swollen joints due to inflammation in the musculoskeletal tissues of the joints. However, although topical administration of certain NSAIDs, such as naproxen, ketoprofen, diclofenac, piroxicam and ibuprofen, has been shown to deliver the drug to the local musculoskeletal tissues of joints where arthritic conditions often develop, due to the low solubility of NSAIDs in water, the effectiveness of topical administration of NSAIDs is limited by the inability of these drugs to permeate the skin.
In the conventional topical formulations of NSAIDs that are commercially available, the active ingredients are simply dissolved, dispersed or otherwise formulated in a suitable pharmaceutical vehicle. The thermodynamic activity of the drug in such formulations is relatively low due to the limited solubility of drugs in the vehicle. In recent years, improvement of the dermal permeation of NSAIDs has been introduced, which includes the increase of lipophilicity of the drug, the incorporation of the drug into lipid vesicles such as liposomes, and the employment of a permeation enhancer in the formulation. However, the results of these approaches are largely unsatisfactory.
Recently, U.S. Pat. No. 6,368,618 B1 discloses a topical formulation for delivery of NSAIDs using a two phase liquid composition containing aqueous and oil phases. U.S. Pat. No. 6,420,394 discloses yet another topical pharmaceutical formulations for NSAIDs, which includes the addition of sodium phosphate buffer and optionally an alcoholic solvent to increase the permeation of NSAIDs. However, based on the facts that the absence of effective transdermal formulations of NSAIDs in the marketplace, efforts directed toward improving the delivery system of NSAIDs are desperately needed.
Contrary to local anesthetics, NSAIDs are weak acid. There are roughly nine major classes of NSAIDs, which are salicylate derivatives (such as acetosalicylate [aspirin]), propionic acid derivatives (such as ibuprofen), aniline derivatives (such as aminophenolacetaminophen [tylenol]), pyrazole derivatives (such as phenylbutazone), N-arylanthranilic acid (or fenamates) derivatives (such as meclofenamate), indole derivatives (such as indomethacin), acetic acid derivatives (such as diclofenac), oxicam derivatives (such as piroxicam), and miscellaneous others (such as celecoxib).
Among the NSAIDs, diclofenac, which is 2-(2,6-dichloro-anilino)-phenyl-acetic acid, is particularly known for its role as an anti-rheumatic agent for treatment of rheumatoid arthritis. Diclofenac belongs to the acetic acid class of NSAID. Due to its relatively low solubility in water, an aqueous injection solution of diclofenac is difficult to achieve.
U.S. Pat. No. 4,711,906 discloses a liquid diclofenac preparation where a better dissolution of the diclofenac is obtained when a local anesthetic, lidocaine, is added. This liquid diclofenac preparation is particularly suitable for use as injection solution.
Another NSAID similar to diclofenac and also belongs to the acetic acid class of NSAIDs is ketorolac. Ketorolac is comparable to opioids in terms of providing pain relief. For example, the overall analgesic effect of 30 mg of ketorolac is equivalent to that of 6 to 12 mg of Morphine.
Ketorolac is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid. It is a derivative of pyrrolizine carboxylic acid and is structurally related to tolmetin and zomepirac. Like diclofenac, the free acid form of ketorolac has very low solubility in water. The most commonly used salt form of ketorolac is ketorolac tromethamine, which is much more water soluble than the free acid form of ketorolac.
There are various dosage forms/formulations for ketorolac tromethamine. For example, U.S. Pat. No. 6,090,368 discloses a pharmaceutical composition comprising ketorolac tromethamine admixed with an aqueous bioadhesive cellulosic polymer containing microcrystalline particles. The pharmaceutical composition is particularly useful for use in nasal spray. U.S. Pat. No. 5,414,011 discloses an ophthalmic formulations consisting of ketorolac alone or in combination with an antibiotic drug, and a preservative system having a quaternary ammonium preservative and a nonionic polyoxyethylated octylphenol surfactant. U.S. Pat. No. 5,883,115 discloses a transdermal delivery of an eutomer of ketorolac.
Ketorolac is a chiral drug which contains racemic mixture of [−]S form and [+]R form. The biological activity of ketorolac is with the S form. An eutomer is the stereoisomer of a chiral drug that exhibits greater pharmaceutical activity than its counterpart stereoisomer. In this case, the eutomer is the S form of ketorolac. U.S. Pat. No. 6,333,044 discloses a therapeutic composition of the racemic active form of ketorolac (i.e., the S form), in combination with a pharmaceutically acceptable excipient or diluent, for use in intranasal administration.
In the invention to be presented below, a group of novel pharmaceutically acceptable salts containing local anesthetic and anti-inflammatory effects is introduced. These pharmaceutically acceptable salts can be categorized as a “NSAID salt of a local anesthetic.” These salts are further characterized by their unique physical and chemical properties, which resemble neither NSAIDs nor local anesthetics that they are originated from. These pharmaceutically acceptable salts not only have improved therapeutic activities for pain relief, but also demonstrate far much better solubility when used in parenteral injection and transdermal permeation when used in topical treatments.